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Antagonistic Epistasis of Hnf4α and Foxo1 Networks Through Enhancer Interactions

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Antagonistic Epistasis of Hnf4α and Foxo1 Networks Through Enhancer Interactions bioRxiv preprint doi: https://doi.org/10.1101/2020.07.04.187864; this version posted July 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Kuo et al, Hnf4a and FoxO1 in b-cell function Antagonistic epistasis of Hnf4α and FoxO1 networks through enhancer interactions in β-cell function Taiyi Kuo1,3,*, Wen Du1, Yasutaka Miyachi1, Prasanna K. Dadi2, David A. Jacobson2, Domenico Accili1 1Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 2Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 3Lead Contact *Correspondence: Taiyi Kuo, Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, 1150 St. Nicholas Avenue, Room 237, New York, New York 10032, USA. Phone: 1-212-851-5333. Email: [email protected]. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.04.187864; this version posted July 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Kuo et al, Hnf4a and FoxO1 in b-cell function Abstract Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components, and are known to act through β-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature β-cells leads to increased selection of FoxO1 enhancers by Hnf4α. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues, was completely reversed in double mutants. Gene expression analyses revealed the reversal of β-cell dysfunction with an antagonistic network regulating glycolysis, including β-cell “disallowed” genes; and that a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction. 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.04.187864; this version posted July 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Kuo et al, Hnf4a and FoxO1 in b-cell function Introduction Genetic predisposition contributes to type 2 diabetes through changes in the expression and activity of transcription factors essential for β-cell function and insulin sensitivity (Ferrannini, 2010). The best characterized examples are the MODY gene mutations, which generally act in autosomal dominant fashion to impair insulin secretion (Fajans and Bell, 2011). In the vast majority of patients, however, such predisposition is more subtle, and requires acquired abnormalities, often associated with altered nutrient utilization, to give rise to overt β-cell dysfunction. An example of acquired transcriptional abnormalities leading to altered β-cell function is FoxO1, a nutrient-regulated transcription factor whose nutrient excess-driven failure leads first to metabolic inflexibility (Kim-Muller et al., 2014), and then to outright β-cell dedifferentiation (Cinti et al., 2016; Sun et al., 2019; Talchai et al., 2012). This is achieved in part by direct actions on glucose metabolism (Kuo et al., 2019b) and in part by regulating lineage stability (Kuo et al., 2019a). We have been interested in exploring the functional relation between FoxO1 and Hnf4α, as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction. When we ablated FoxO1, 3a and 4 in pancreatic progenitors or mature β-cells, gene ontology analyses revealed that Hnf4α targets were the most altered (Kim-Muller et al., 2014). However, whether these changes resulted in activation or repression of Hnf4α, and whether they contributed to, or offset FoxO1-induced β-cell dysfunction, was not clear. Mutations of HNF4A cause MODY1 (Yamagata et al., 1996). Most patients develop diabetes in the third decade of life owing to a primary defect in insulin secretion (Herman et al., 1994) that can be treated long-term with sulfonylureas (Gardner and Tai, 2012). In mice, pancreas-wide (Pdx1-Cre) or mature β-cell (Rip-Cre) deletion of Hnf4α causes glucose intolerance due to defective insulin secretion (Boj et al., 2010; Gupta et al., 2005; Miura et al., 2006). There are shared phenotypic features between FoxO-deficient and Hnf4α-deficient β- 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.04.187864; this version posted July 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Kuo et al, Hnf4a and FoxO1 in b-cell function cells (Gupta et al., 2005; Kim-Muller et al., 2014; Miura et al., 2006) that include compromised glucose-stimulated insulin secretion, and altered Pparα and Hnf1α gene network expression, indicative of shared pathways and targets of both transcription factors. The present studies were undertaken to analyze a potential FoxO1/Hnf4α epistasis. Surveys of histone H3 lysine 27 acetylation for active promoters and enhancers uncovered an interplay between Hnf4α and FoxO1 at β-cell enhancers. Thus, we generated and compared mutant animals lacking FoxO1, Hnf4α, or both in β-cells. Surprisingly, FoxO1/Hnf4α double knockout mice (DKO) showed restored glucose tolerance and insulin secretion compared to single knockouts. These findings fundamentally change our understanding of the interactions within transcriptional networks regulating β-cell function by highlighting a heretofore unrecognized antagonistic epistasis (Snitkin and Segre, 2011). 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.04.187864; this version posted July 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Kuo et al, Hnf4a and FoxO1 in b-cell function Results Altered enhancer selection in β-cell failure Activation of FoxO1 enhancers is a key event in β-cells in response to insulin-resistant diabetes in db/db mice (Kuo et al., 2019b). We investigated FoxO1-regulated enhancers in a multiparity model of diabetes associated with genetic ablation of FoxO1 (Kuo et al., 2019a; Talchai et al., 2012). To this end, we subjected fluorescently sorted β-cells from multiparous diabetic β-cell-specific FoxO1 knockout mice (DM) and glucose-tolerant controls (NGT) to genome-wide chromatin immunoprecipitation with acetylated histone 3 lysine 27 antibodies (H3K27ac) as a marker of active enhancers and promoters (Creyghton et al., 2010). DM mice show evidence of multiparity-associated β-cell failure with random as well as re-fed hyperglycemia as well as fasting and refed hypoinsulinemia (Kuo et al., 2019a; Talchai et al., 2012). We observed a global increase of H3K27ac in active regions (Fig. S1A), and in individual genes (Fig. S1B) of DM β-cells. Nearly half (44%) of H3K27ac peaks were located in introns, 14% in intergenic regions, and 16% in promoters (Fig. S1C). We analyzed the data based on H3K27ac regions associated with promoters (defined as +/– 3kb from transcription start sites) or distal enhancers (defined as beyond promoters) (Lenhard et al., 2012). Interestingly, we detected significant changes in distal enhancers in the absence of FoxO1, regardless of age or parity (Fig. 1A). In contrast, we found minimal alterations in the promoters (Fig. 1B). These data confirm the importance of FoxO1 in distal enhancers (Kuo et al., 2019b). To investigate the functional consequences of the altered distal enhancer profile of DM β-cells, we mined transcription factor binding motifs in regions with increased or decreased H3K27ac marks in DM vs. NGT. We reckoned that activation of transcription factors would be associated with enrichment of the relevant motifs in hyper-acetylated enhancers, whereas suppression of transcription factors would be associated with enrichment of their motifs in hypo- acetylated enhancers (Kuo et al., 2019b). FoxO1 was the second most-underrepresented motif 5 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.04.187864; this version posted July 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Kuo et al, Hnf4a and FoxO1 in b-cell function found within hypo-acetylated enhancers in DM β-cells, thus validating the analysis (Fig. 1C). We also found a significant depletion of the Pax6 motif, a FoxO1 target (Kim-Muller et al., 2016b; Kitamura et al., 2009) that regulates Ins1, Ins2 (Sander et al., 1997), Nkx6.1, Pdx1, Slc2a2 and Pc1/3 in β-cells (Hart et al., 2013). Pax6 represses alternative islet cell genes including ghrelin, glucagon, and somatostatin (Swisa et al., 2017), and ablation of Pax6 in the adult pancreas leads to glucose intolerance due to β-cell dedifferentiation (Hart et al., 2013; Swisa et al., 2017).
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